A common feature of retrovirus replication is reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of human immunodeficiency virus (HIV) sequences. Therefore, reverse transcriptase is a clinically relevant target for the chemotherapy of retroviral infections.
It is known that a number of benzoxazinone compounds are effective in the treatment of HIV which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Among them, the (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of Formula 1 (Efavirenz) is not only a highly potent reverse transcriptase inhibitor, but also efficacious against HIV reverse transcriptase resistance.

U.S. Pat. No. 5,519,021 discloses certain benzoxazinones that are useful in the inhibition of HIV reverse transciptase (including its resistant varieties), the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
In U.S. Pat. No. 5,633,405 an improved synthesis of a highly potent HIV reverse transcription inhibitor is disclosed, involving an acetylide and a trifluoromethyl ketone which produces a chiral product in the presence of a chiral amino alcohol. See also Tetrahedron Lett. 1995, 36, 8937 and J. Org. Chem. 1998, 63, 8536.
U.S. Pat. No. 5,922,864 discloses an efficient method for the preparation of a compound of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3, 1-benzoxazin-2-one, also known as DMP-266, a reverse transcriptase inhibitor using a cyclization reaction of the amino alcohol intermediate with an alkyl or aryl chloroformate and a base.
U.S. Pat. No. 5,925,789 provides novel methods for the asymmetric synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of Formula 1 which is useful as a human immunodeficiency virus (HIV) reverse transcriptase inhibitor.
U.S. Pat. No. 5,952,528 discloses a process for enhancing the purity of 2R-[1-hydroxy-1-trifluoromethyl-3-cyclopropylpropyn-2-yl]-4-chloroaniline comprising the formation of an acid addition salt which is capable of rejecting the racemate in the selected organic solvent.
U.S. Pat. No. 6,015,926 discloses an efficient method for the preparation of key intermediate, in the synthesis of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, a reverse transcriptase inhibitor is achieved using a chiral addition reaction to the 4-chloro-2-trifluoromethylketoaniline with an organozinc complex to give the desired alcohol. This instant method has broad applicability in the chiral addition to any prochiral ketone.
U.S. Pat. No. 7,205,402 provides novel methods for the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of Formula 1 which is useful as a human immunodeficiency virus (HIV) reverse transcriptase inhibitor.
U.S. Pat. No. 7,439,400 disclosed a new process of asymmetric alkynylation of ketone or ketimine, involving the chiral ligand-mediated asymmetric addition of zinc or copper acetylide to a trifluoromethyl ketone or ketimine intermediate to give a chiral tertiary propargylic alcohols or amines. The adduct compounds include the key precursors to the potent HIV reverse transcriptase inhibitor Efavirenz (DMP 266), DPC 961 and DPC 083. The invention also disclosed a novel chiral amino ligand.